In this study, we investigated the effect of antenatal allopurinol (ALLO) treatment on levels and expression of plasticity markers in the dorsal hippocampus of low (LBW) and normal (NBW) birth weight piglets. ALLO treatment given daily in the last trimester to pregnant sows had a protective effect on neuronal plasticity markers in their piglets. ALLO increases protein levels of BDNF and the postsynaptic marker PSD95 in LBW and NBW piglets. ALLO treatment increases the pCREB/CREB ratio in LBW piglets to a similar level as that found in untreated NBW piglets. In conclusion, antioxidant treatment administered in the last trimester might be a promising treatment for LBW neonates.